Basic questions posed by the therapeutic effect of lithium (Li ion) in manic-depressive illness include: What is the cellular defect in this illness? What is the mechanism underlying Li ion's therapeutic effect? How can the efficacy of Li ion therapy be improved? In previous years of this project, we developed a microanalytical technique for Li ion and related cations several orders of magnitude more sensitive than existing methods. We used this technique to assess how four major flux pathways contribute to Li ion transport in normal human erythrocytes (RBCs); and how Li ion affects transport of neurotransmitter precursors in RBC, choroid plexus, blood-brain barrier, and arachnoid. We discovered that Li ion increases RBC choline concentrations 10-fold and decreases choline turngver in brain. Analysis of Li ion pharmacokinetics in normal individuals yielded estimates of Li ion intestinal absorption, renal excretion, exchange across RBC and muscle membranes, and Li ion content in RBC and muscle. We nowpropose four new classes of experiments: 1. Studies of RBC as a model cell system, to determine the identify of the Li ion carrier, the mechanisms of Li ion effects on membrane transport, and whether transport changes with mood state. 2. Analysis of Li ion pharmacokinetics in manic-depressives on Li ion therapy, to understand muscular and intestinal side-effects of Li ion, and to devise optimized dose regimens. 3. Study of regional variation in Li ion abosorption along the human intestine, as background to decreasing an effective slow-time-release preparation. 4. Measurement of Li ion transport and Li ion effects in the membranes regulating the extracellular fluid of the brain.